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SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The...

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Autores principales: Higgs, Matthew H., Jones, James A., Wilson, Charles J., Beckstead, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088984/
https://www.ncbi.nlm.nih.gov/pubmed/36973012
http://dx.doi.org/10.1523/ENEURO.0445-22.2023
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author Higgs, Matthew H.
Jones, James A.
Wilson, Charles J.
Beckstead, Michael J.
author_facet Higgs, Matthew H.
Jones, James A.
Wilson, Charles J.
Beckstead, Michael J.
author_sort Higgs, Matthew H.
collection PubMed
description Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input–output properties of pacemaking neurons can be characterized by the phase-resetting curve (PRC), which describes the sensitivity of interspike interval (ISI) length to inputs arriving at different phases of the firing cycle. Here we determined PRCs of putative DA neurons in the substantia nigra pars compacta in brain slices from male and female mice using gramicidin-perforated current-clamp recordings with electrical noise stimuli applied through the patch pipette. On average, and compared with nearby putative GABA neurons, DA neurons showed a low, nearly constant level of sensitivity across most of the ISI, but individual cells had PRCs showing relatively greater sensitivity at early or late phases. Pharmacological experiments showed that DA neuron PRCs are shaped by small-conductance calcium-activated potassium and Kv4 channels, which limit input sensitivity across early and late phases of the ISI. Our results establish the PRC as a tractable experimental measurement of individual DA neuron input–output relationships and identify two of the major ionic conductances that limit perturbations to rhythmic firing. These findings have applications in modeling and for identifying biophysical changes in response to disease or environmental manipulations.
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spelling pubmed-100889842023-04-12 SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons Higgs, Matthew H. Jones, James A. Wilson, Charles J. Beckstead, Michael J. eNeuro Research Article: New Research Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input–output properties of pacemaking neurons can be characterized by the phase-resetting curve (PRC), which describes the sensitivity of interspike interval (ISI) length to inputs arriving at different phases of the firing cycle. Here we determined PRCs of putative DA neurons in the substantia nigra pars compacta in brain slices from male and female mice using gramicidin-perforated current-clamp recordings with electrical noise stimuli applied through the patch pipette. On average, and compared with nearby putative GABA neurons, DA neurons showed a low, nearly constant level of sensitivity across most of the ISI, but individual cells had PRCs showing relatively greater sensitivity at early or late phases. Pharmacological experiments showed that DA neuron PRCs are shaped by small-conductance calcium-activated potassium and Kv4 channels, which limit input sensitivity across early and late phases of the ISI. Our results establish the PRC as a tractable experimental measurement of individual DA neuron input–output relationships and identify two of the major ionic conductances that limit perturbations to rhythmic firing. These findings have applications in modeling and for identifying biophysical changes in response to disease or environmental manipulations. Society for Neuroscience 2023-04-07 /pmc/articles/PMC10088984/ /pubmed/36973012 http://dx.doi.org/10.1523/ENEURO.0445-22.2023 Text en Copyright © 2023 Higgs et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: New Research
Higgs, Matthew H.
Jones, James A.
Wilson, Charles J.
Beckstead, Michael J.
SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons
title SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons
title_full SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons
title_fullStr SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons
title_full_unstemmed SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons
title_short SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons
title_sort sk and kv4 channels limit spike timing perturbations in pacemaking dopamine neurons
topic Research Article: New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088984/
https://www.ncbi.nlm.nih.gov/pubmed/36973012
http://dx.doi.org/10.1523/ENEURO.0445-22.2023
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